Good afternoon, everyone. Thanks for joining Jefferies Healthcare Conference in London. My name is Clara Don. I'm one of the biotech analysts here at Jefferies. Sitting next to me is Dr. Pravin Dugel, Executive Chair, President, and Chief Executive Officer at Ocular Therapeutix. Welcome.
Thank you, Clara. Thank you for having us here.
Maybe before we discuss the specifics, maybe just give us a high-level overview of Ocular. A lot has been going on, a lot of great momentum at Ocular in the past few years. What has kept you busy for the past 12 months?
There is a lot that has kept us busy. We are in a pivotal moment at this point that we are very, very excited about. As you know, we have two phase III programs that are going on that are designed in a fairly unique and complementary fashion. We have a study called the SOL-1 study, which is a superiority study. The card turn of that study, as we have announced, will be in the first quarter of 2026. We have another study, which is a non-inferiority study called SOL-R. We have announced the card turn for that, having given ourselves quite a bit of leeway. It is going to be in the first half of 2027. We are extremely excited about both studies. We believe that we have executed both studies to the best of our abilities. We are very happy with the way the execution has come up so far.
We are very excited and want to see the card turn for SOL-1. We could not be happier with what we have done so far.
Let's just go directly into AXPAXLI, your lead program for retinal diseases. Maybe give the audience a little bit of background on AXPAXLI. What are the indications that AXPAXLI is focusing on, what are the unmet needs, and how AXPAXLI can address those unmet needs in that field?
AXPAXLI consists of a TKI on an attunable hydrogel platform. We've had studies that have been done in Australia as well as in the U.S. that have shown very encouraging results. The reason that we're so excited about AXPAXLI is not only the data that we've seen, but also the de-risk nature of this drug. This drug will inhibit VEGF, amongst other receptors as well. It is the most potent TKI that is being developed, more potent than any other by about 100-fold, and more selective than any other by about 50-fold. This is a TKI that is, again, an attunable hydrogel platform so that when the drug is gone, the hydrogel is also gone. There's really nothing left behind. There are no carcasses floating around. Both of them are gone at the same time.
What this will do is, we believe, allow for a new standard of care in retina. We're starting with wet macular degeneration. Recently, we've also announced that we'll be launching into diabetic retinopathy. With wet macular degeneration, what we know is that despite having an effective treatment, which is the inhibition of VEGF, in the U.S. alone, in the first year, there's a 40% dropout rate. Just think about that. There's a 40% dropout rate. That means that 40% of patients who could be treated are going blind. The reason for that is the unsustainable nature of the treatment, which requires coming in for an injection every month or every other month. We believe that we'll be able to tackle that with a known target in a de-risked fashion. We believe that this will be the standard of care.
As far as diabetic retinopathy is concerned, at this point, we know that there is a receptor where, if you inhibit that receptor, which is also VEGF, the outcome is excellent. In fact, there are two drugs, Eylea and Lucentis, that are labeled for diabetic retinopathy. However, it's not used at all. Less than 1% of patients are getting treated. The reason for that, again, is sustainability. Patients have to come in every month or every other month, and they simply can't. What we have shown in one of our studies, the Healio study, is that if you go ahead and inject our drug once a year, the chance of having a blinding complication, a vision-threatening complication, goes from about 40% to literally zero once a year. That, we believe, is absolutely sustainable. That's like going to your dentist for teeth cleaning once a year.
We're very excited about AXPAXLI, both in wet macular degeneration as well as diabetic retinopathy and diabetic macular edema.
Maybe let's stay focused on wet AMD first. You talk about two pivotal trials, SOL-1 and SOL-R. The word confidence actually came up repeatedly when we hear you talk about those two pivotal trials recently. Maybe just share the reasons behind that confidence, particularly from the perspective of your clinical trial design in wet AMD.
The confidence comes at several levels. First of all, when you look at the drug itself, as we've described, we're inhibiting a known receptor that's known to work. There is a lot of de-risking there. We're not reinventing the wheel. We've known for 40 years that inhibiting VEGF works in wet macular degeneration. That's exactly what we're doing, plus other receptors as well. That gives us a great deal of confidence as far as de-risking is concerned. The other part is we have studies. We have studies that have been done in Australia. We have studies that have been done in the U.S. that have shown us that with a single injection, the rescue-free rate at six months is 100%. 100% of patients did not require any rescue at six months, and 80% of patients did not require any rescue at 12 months.
We're very confident that we will beat our control, which is a single injection of Eylea. The trial design gives us a great deal of confidence, and the data that we have before gives us a great deal of confidence. The other part of this, which is really important, is patient selection. We have gone out of our way to have a de-risked patient population selected that is bespoke for each trial. For the first study, which is SOL-1, we specifically selected patients that did not have any fibrosis. These are treatment-naive patients who are designed to be VEGF-dependent, selected to be VEGF-dependent. We went ahead and loaded them up and allowed them to fail once. That's the rescue criteria, which is 15 letters of loss. We specifically de-risked that patient population.
As we de-risked the patient population in SOLAR, which is the non-inferiority study, where patients were selected specifically to be stable. The third thing is what we see under masking right now. I've said repeatedly that I'm thrilled at the way this trial is being executed. I'm referring to the superiority study, SOL-1. We're looking at three parameters. We're looking at the number of rescues. We're looking at the cadence or the pattern of rescues. We're also looking to see if those rescues are on protocol or not. What we've recently announced in our investor day is that over 95% of rescues are on protocol. That's unheard of. No other retina study has had that accomplished. We also announced that over 95% of patients are being retained. That's also unheard of.
What we're doing is we're executing these trials in the highest probable manner as well as possible. All of those things give me a great, great deal of confidence, more than ever, in the outcome of these studies.
Great. I also want to talk about the superiority design for your SOL-1. Maybe just talk to us, what's the significance of superiority label in wet AMD?
That's a great question. Look, first of all, the superiority design of this study was not designed by us. What we have done is to follow the FDA guidelines exactly for both of our studies. Remember, for SOL-1, we've been rewarded with a SPA, which is the highest level of engagement, as you know, with the FDA. This is an FDA path for superiority. We believe that our label will read as follows. We believe that we will have the first and only superiority label versus an anti-VEGF. We believe that our label will have the flexibility of dosing every six months to every 12 months based on both of those studies. We believe our label will also have repeatability. Very importantly, this will not be in the label, but this will be for our commercial use.
We will also be able to show superiority versus the second generation VEGF, which is HD Eylea. That will be not on label because that is a numeric analysis that we will do, not a statistical analysis. Back to your question, what is the significance of having a superiority label? The significance is that it is really the Holy Grail. If you look at every other study that has been done and being done, these are non-inferiority studies. There are lots and lots and lots of anti-VEGF drugs. Now we have biosimilars. We will have generics, et cetera. There is a race to the bottom in terms of pricing. There is step therapy, et cetera. We will be immune from all of those things because we will be the only one with a superiority label. In fact, it is not just the superiority label, but we will back that up with data.
The data is the open label extension. The most important part about the open label extension is the crossover patients. These patients will be crossed over after two years of pulsatile therapy. We do not think those patients will ever catch up. The reason for that is because they will develop fibrosis. We know that fibrosis develops within 90 days. That is detectable. After two years, we believe that those patients will have enough fibrosis that they will never catch up. Now we will have this drug with a superiority label that is a premium drug. We will have long-term data to show that to get the best outcomes possible, you have to start on this premium drug from the very beginning. The third part of the triad is our IP. We now have an IP extension to 2044.
Those three things make this drug in an entirely different orbit and very attractive indeed. Now, if you ask your KOLs, as people do, does a superiority label matter? Most KOLs, as I used to when I was practicing, say no. I never look at a label when I inject. That's true. That's what I used to say as well. That's the wrong question to ask. The right question to ask is, does it matter to you that you get to choose the drug that you want from the very beginning? Does it matter to you that you don't have to do step therapy and watch your patient fail on a lesser drug before you can petition for the drug that you want? Does it matter to you that you get the highest ASP and the most reimbursement possible from a drug?
At the end of the day, every KOL will say yes to all of those questions. That is because of a superiority label.
For SOL-1, what's the delta you need to see for achieving superiority from a statistical perspective?
The delta is getting statistical significance, which we believe is about 15% or so. It is a great question. Let me just say what we need to do and what we need to see in the cartoon of SOL-1. The fact of it is that the purpose of SOL-1 is to get a superiority label. The purpose of SOL-R is to be clinically relevant. What we have in SOL-1 is a fantastic regulatory endpoint that will allow us, as I've said before, a superiority label. However, it is not necessarily clinically relevant to a great degree because in truth, people really do not wait to see a 15-letter loss. What we need to do is not just announce that we've hit a primary endpoint because that is not going to be sufficient. Now, I'm confident we will, but that is not going to be sufficient.
What we need to do is to go ahead and extract data from SOL-1 that will give you a line of sight into SOL-R. In other words, we'll give you even more confidence that SOL-R will be positive. We understand that challenge. We accept that challenge. That's exactly what we'll do.
For SOL-R, you recently announced a completion of randomization for 555 subjects. Maybe tell us a little bit more about your prior assumptions for SOL-R and the FDA-agreed non-inferiority margin.
Yeah. What we announced was that we had recruited enough patients that we will fulfill that goal. That's exactly right. What we have, again, going back to de-risking SOL-R, which is a great question, starts with patient selection. In SOL-R, we have a non-inferiority study. What you want in a non-inferiority study is absolute stability. If you look at any anti-VEGF chart where you graph the number of injections versus vision, it all looks absolutely identical. After about two or three injections, the vision continues to go up, and then it simply stabilizes from that point on with all the other injections. What we could have done is simply say we're going to give two or three injections, and then we're going to randomize, assuming those patients will be stable. That's not what we did. We went above and beyond.
What we said is we're going to go ahead and have treatment-naive patients. We're going to give them three injections, right, so in the upper half of that curve where we're already stable. Then we're going to have two months' worth of observation. That's absolutely unique. What we're observing for is we're observing for any kind of fluctuation whatsoever. Any patient with fluctuations in terms of OCT or vision will be weeded out. When we assure stability, there'll be two more injections, and only then do we randomize. It's a very, very long ramp. It's a six-month ramp with a unique two-time opportunity to go ahead and watch for fluctuations. We've done that specifically to de-risk the patient population and randomize only those patients that are absolutely stable. That's one factor. The other factor is the endpoint.
We have a primary endpoint that we believe is absolutely optimal for us. It's a singular endpoint. It's not a blended endpoint. When you have an optimal endpoint for you, you don't want it blended. You don't want it to be diluted. We have a singular endpoint at week 56. We believe those two things absolutely de-risk the SOL-R trial. We will also provide further information for you from SOL-1. As I mentioned, we're committed to do that to show you that we've de-risked it even further.
I also want to quickly touch on the rescue criteria in SOL-1. Maybe just tell us, how does the criteria you're using reflect the real-world practice?
In SOL-1?
SOL-R.
In SOL-R.
Yes.
The rescue criteria in SOL-R right now is five letters and 75 microns. What we have done is to go ahead and amend that to be very generic and simple for the simple reason that we invite comparisons. We're absolutely confident that the number of rescues will beat any previous study. To invite comparisons, we've made the rescue criteria such that it can be compared to previous studies. What we've also done, the second reason for amending that rescue criteria, is because now we're completely aligned with OUS regulatory agencies because we're using the same criteria that they've seen before and they've approved before. It made sense for us to go ahead and amend the rescue criteria. Again, we're absolutely confident in the stability of patients we're randomizing. We believe that we'll have fewer rescues than any other studies before.
We invite comparisons, and that's why we amended the criteria.
Following the readouts from SOL-1 and SOL-R, how should we think about the timeline for regulatory submission? You mentioned in the past about a 505(b)(2) pathway. Maybe just tell us, how does this pathway work, and how does that accelerate your submission process?
Yeah. We expect the FDA to continue to require two positive phase three studies for approval. We intend to submit for approval immediately after a successful SOL-R study, the second study, which is at week 56. We believe that our filing will be very efficient for two reasons. On the front end, we have a product consisting of two components, each of which is already FDA approved, the TKI as well as the hydrogel. They're both already FDA approved independently. We will be filing what's called a 505(b)(2). That means that we will save about two months in the front end because they already have the safety data available to them. The FDA does. On the back end, we believe that we'll be very efficient because we have a SPA. That means that the FDA has already approved the SAPs and everything else.
We believe that our submission process for approval will be very efficient.
Let's talk about NPDR and DME as well. You recently announced your pivotal plan for AXPAXLI in those two indications. For those who might be less familiar with those two, can you just talk about how large exactly is this opportunity for AXPAXLI?
First of all, as I said, the target size for diabetic retinopathy is three and a half times that of wet macular degeneration, and less than 1% of patients are treated. That is basically nobody being treated. Understand that these patients are at risk. Year upon year, 30-40% chance of having a blinding complication year upon year. What we have done is we have data from a phase one study called Helios that we think is absolutely remarkable. Every single parameter was aligned in favor of the drug after a single injection, a single injection at week 48.
That means that you can sit there if these studies hold, and we think they will, that means that you can sit there, look at somebody in the eye, and say, "You know, your chance of having a blinding complication because of this horrible disease is 30-40% year upon year. Now, if you come to see me but once a year, like you go to a dentist for teeth cleaning, I can reduce that risk literally to zero." That's compelling. That's sustainable. What we've done is design a very, very efficient program where we will be recruiting patients with non-proliferative diabetic retinopathy as well as non-center-involving diabetic macular edema.
We believe we'll be successful based on not only the previous studies that I mentioned, but also on a novel endpoint that we call the ordinal endpoint, which allows for credit in three ways: maintaining vision, improving vision, as well as stopping the diabetic retinopathy score from getting worse. I'm sorry, not vision. It's the diabetic retinopathy score. It's a novel endpoint, and we believe that it's optimized in our favor. Given that and given the fact that we're including patients with non-center-involving diabetic macular edema, we believe that we're in line to get a broad label that includes all of diabetic retinal disease. We don't think that we'll ever have to do another diabetic retinopathy study again because we believe the label will include diabetic retinopathy as well as diabetic macular edema. Remember, every patient with diabetic macular edema does have diabetic retinopathy as well.
This will change the way this disease is managed. The target opportunity is massive. We believe that this novel endpoint, which is the ordinal DRSS, as we call it, is going to be something that all studies for diabetic retinopathy will use from this point on.
Since you mentioned the ordinal primary endpoint you use for Helios program, maybe talk about this. Do you have FDA agreement for this primary endpoint use, and what feedback have you heard from them?
We absolutely do. Let me just describe what that is. What we have suggested to the FDA is to say, "Look, you are asking us to pick one of two different things: a two-step difference, which is a photographic objective difference called the diabetic retinopathy severity score, whether the drug will improve by two steps or stop the decline by two steps." You cannot pick both. You have to pick one or the other. That was the way it was done previously. We have suggested to the FDA to say, "Look, in this disease, which is a blinding disease that progresses inevitably, it matters if a drug improves your diabetic retinopathy score. It also matters if the drug stops it from getting worse, but it also matters if the drug maintains it. All three should count." Each patient should have really three shots on goal.
Now you can see the powering goes up immensely. Our chance of success, we believe, goes up immensely as well. We also believe that it's absolutely clinically much more relevant. The FDA, thankfully, has accepted that. It's not only accepted, but it's validated by a SPA. We believe that we're very likely to follow through with success in both Helios 2 as well as Helios 3 with this novel endpoint.
How do you plan to leverage Helios 2 and Helios 3 data for future DME opportunities since you're not running a separate DME trial for AXPAXLI?
Remember, what we're doing is we are including patients with non-center-involving diabetic macular edema. As you know, what the FDA does is, as far as labeling is concerned, they give labels based on the disease itself. A good example is my last company. In my last company, Iveric Bio, we studied geographic atrophy. As you will remember, Clara, we did not study a single patient with center-involving geographic atrophy, not a single patient, right? This came up. People used to say, "You know, your label is going to be restricted only for non-center-involving geographic atrophy." Guess what? It wasn't. The label is very broad. It's disease-based. It includes all of geographic atrophy. This has been seen over and over and over again. If you look at Anchor & Marina, way back with Lucentis, there was a vision restriction.
There is no vision restriction in the Lucentis or Eylea label with View 1 and View 2 or Anchor & Marina. If you look at Panorama, which is the diabetic retinopathy study for Eylea, there was a restriction based on the DRSS score. There is no restriction in the label. It is a broad disease-based label. I believe that what we will have, similarly, because of history and because of our conversations with the FDA and so forth, is a broad label that will include all of diabetic retinopathy and diabetic macular edema. Remember, every patient with diabetic macular edema also has diabetic retinopathy. There is no patient who has diabetic macular edema that does not have diabetic retinopathy. All of these patients will be using our drug. I do not believe we will ever have to do another diabetic retinopathy study again.
I think we'll cover all of diabetic retinal disease.
For the last minute, can we also talk about your commercial product?
We have a product called Dextenza, which we're very happy with. The hydrogel is exactly the same. It's tuned to last for one month. We are very happy with it. We're also very happy that we have a commercial team that's used to scaling up and selling this product. There's a great deal of overlap, as you know, in ophthalmology. It's very, very valuable for us to have a commercial team that's already in ophthalmology and already used to selling products to ophthalmologists. We believe that bolting on a retina product in this commercial team will be quite easy and seamless.
Lastly, for wet AMD and NPDR and DME, would you consider any partnership for launch?
You know, I don't think there's any need to at this point. The only reason for partnership would be if you need money or if you need expertise. We have an ample amount of both. We're very well capitalized to commercialize this product ourselves. We certainly have more expertise in retina than any other company per capita in the planet. So I don't think there's any need whatsoever at this point for partnership or licensing opportunities. We're very well set up to go ahead and do this by ourselves.
Thank you. That concludes our session here. Thank you so much for being here. Thank you, everyone, for joining us here in person and online.
Thank you.
Enjoy the rest of the conference.
Thank you very much, Clara. Thank you for having us.
Thank you.